The goal of this proposal is to elucidate the roles of cyclin-dependent kinase inhibitor p27 in cancer and its regulation by oncogenic signals. p27 is a new class of tumor suppressor and is haplo-insufficient in tumor suppression. Decreased expression of the p27 protein was shown to correlate with cancer development and poor survival rates, and is an important marker of cancer progression. Overexpression of HER2, a proto-oncogene, was reported to correlate with poor survival rates in cancer patients. Many cancers affected by HER2 overexpression, including breast, colon, gastric, lung, and ovarian cancers, are the cancers with decreased p27 expression. Little is known about the possible link between HER2 overexpression and low p27 expression in cancers. Based on the low level expression pattern of p27 in HER2-overexpressing breast cancer samples and cancer cell lines, we hypothesize that a link between these two important prognostic markers exists. Our studies showed that HER2 oncogenic signals cause enhanced ubiquitin-mediated p27 degradation and can lead to nuclear exporting of Jab1/p27 complex. Also, we showed that p27 expression in HER2-overexpressing mouse-derived tumors reduces the tumor volumes in a mouse model. To further understand the molecular mechanism of the regulation between these two important prognostic markers, we will determine the mechanism of HER2-mediated p27 degradation by characterizing the molecular regulation of Jabi, a p27 exporter, and SCF-SKP2 ubiquitin ligase complex in response to HER2 activity. Finally, we will explore the tumor expression activity of p27 to find an optimal therapeutic strategy for HER2-overexpressing breast cancers. We expect that these studies will greatly enrich our understanding of HER2-mediated p27 degradation in cancer and will help develop p27 as a novel therapeutic agent for HER2-associated cancers.